Comparison of Sodium-Glucose Cotransporter-2 Inhibitor and Glucagon-Like Peptide-1 Receptor Agonist Prescribing in Patients With Diabetes Mellitus With and Without Cardiovascular Disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in patients with type 2 diabetes mellitus (T2DM). We sought to describe trends in prescribing for SGLT2is and GLP1-RAs in diverse care settings, including (1) the outpatient clinics of a midwestern integrated health system and (2) small- and medium-sized community-based primary care practices and health centers in 3 midwestern states. We included adults with T2DM and ≥1 outpatient clinic visit. The outcomes of interest were annual active prescription rates for SGLT2is and GLP1-RAs (separately). In the integrated health system, 22,672 patients met the case definition of T2DM. From 2013 to 2019, the overall prescription rate for SGLT2is increased from 1% to 15% (absolute difference [AD] 14%, 95% confidence interval [CI] 13% to 15%, p <0.01). The GLP1-RA prescription rate was stable at 10% (AD 0%, 95% CI -1% to 1%, p = 0.9). In community-based primary care practices, 43,340 patients met the case definition of T2DM. From 2013 to 2017, the SGLT2i prescription rate increased from 3% to 7% (AD 4%, 95% CI 3% to 6%, p <0.01), whereas the GLP1-RA prescription rate was stable at 2% to 3% (AD 1%, 95% CI -1 to 1%, p = 0.40). In a fully adjusted regression model, non-Hispanic Black patients had lower odds of SGLT2i or GLP1-RA prescription (odds ratio 0.56, 95% CI 0.34 to 0.89, p = 0.016). In conclusion, the increase in prescription rates was greater for SGLT2is than for GLP1-RAs in patients with T2DM in a large integrated medical center and community primary care practices. Overall, prescription rates for eligible patients were low, and racial disparities were observed.

Advance Care Planning in Older Adults with CKD: Patient, Care Partner, and Clinician Perspectives.

BACKGROUND: Older patients with advanced CKD are at high risk for serious complications and death, yet few discuss advance care planning (ACP) with their kidney clinicians. Examining barriers and facilitators to ACP among such patients might help identify patient-centered opportunities for improvement. METHODS: In semistructured interviews in March through August 2019 with purposively sampled patients (aged ≥70 years, CKD stages 4-5, nondialysis), care partners, and clinicians at clinics in across the United States, participants described discussions, factors contributing to ACP completion or avoidance, and perceived value of ACP. We used thematic analysis to analyze data. RESULTS: We conducted 68 semistructured interviews with 23 patients, 19 care partners, and 26 clinicians. Only seven of 26 (27%) clinicians routinely discussed ACP. About half of the patients had documented ACP, mostly outside the health care system. We found divergent ACP definitions and perspectives; kidney clinicians largely defined ACP as completion of formal documentation, whereas patients viewed it more holistically, wanting discussions about goals, prognosis, and disease trajectory. Clinicians avoided ACP with patients from minority groups, perceiving cultural or religious barriers. Four themes and subthemes informing variation in decisions to discuss ACP and approaches emerged: (1) role ambiguity and responsibility for ACP, (2) questioning the value of ACP, (3) confronting institutional barriers (time, training, reimbursement, and the electronic medical record, EMR), and (4) consequences of avoiding ACP (disparities in ACP access and overconfidence that patients' wishes are known). CONCLUSIONS: Patients, care partners, and clinicians hold discordant views about the responsibility for discussing ACP and the scope for it. This presents critical barriers to the process, leaving ACP insufficiently discussed with older adults with advanced CKD.

Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease.

Iron deficiency, anemia, hyperphosphatemia, and increased fibroblast growth factor 23 (FGF23) are common and interrelated complications of chronic kidney disease (CKD) that are linked to CKD progression, cardiovascular disease and death. Ferric citrate is an oral phosphate binder that decreases dietary phosphate absorption and serum FGF23 concentrations while increasing iron stores and hemoglobin in patients with CKD. Here we compared the effects of ferric citrate administration versus a mineral sufficient control diet using the Col4a3 knockout mouse model of progressive CKD and age-matched wild-type mice. Ferric citrate was given to knockout mice for four weeks beginning at six weeks of age when they had overt CKD, or for six weeks beginning at four weeks of age when they had early CKD. Ten-week-old knockout mice on the control diet showed overt iron deficiency, anemia, hyperphosphatemia, increased serum FGF23, hypertension, decreased kidney function, and left ventricular systolic dysfunction. Ferric citrate rescued iron deficiency and anemia in knockout mice regardless of the timing of treatment initiation. Circulating levels and bone expression of FGF23 were reduced in knockout mice given ferric citrate with more pronounced reductions observed when ferric citrate was initiated in early CKD. Ferric citrate decreased serum phosphate only when it was initiated in early CKD. While ferric citrate mitigated systolic dysfunction in knockout mice regardless of timing of treatment initiation, early initiation of ferric citrate also reduced renal fibrosis and proteinuria, improved kidney function, and prolonged life span. Thus, initiation of ferric citrate treatment early in the course of murine CKD lowered FGF23, slowed CKD progression, improved cardiac function and significantly improved survival.

DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease.

During chronic kidney disease (CKD), alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality. The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization, but its effects in CKD are unknown. We tested the hypothesis that DMP1 supplementation in CKD would improve bone health, prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes. We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3-/- mouse model of CKD. Col4a3-/- mice demonstrated impaired kidney function, reduced bone DMP1 expression, reduced bone mass, altered osteocyte morphology and connectivity, increased osteocyte apoptosis, increased serum FGF23, hyperphosphatemia, left ventricular hypertrophy (LVH), and reduced survival. Genetic or pharmacological supplementation of DMP1 in Col4a3-/- mice prevented osteocyte apoptosis, preserved osteocyte networks, corrected bone mass, partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription, and further increased serum phosphate. Despite impaired kidney function and worsened hyperphosphatemia, DMP1 prevented development of LVH and improved Col4a3-/- survival. Our data suggest that CKD reduces DMP1 expression, whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.

Fibroblast Growth Factor 23 Trajectories in Chronic Hemodialysis Patients: Lessons from the HEMO Study.

BACKGROUND: Long-term patterns of fibroblast growth factor 23 (FGF23) are poorly characterized among dialysis patients. OBJECTIVES: To identify different FGF23 trajectories and determine clinical factors that predict distinct FGF23 trajectories and whether FGF23 trajectories differ in regard to their associations with all-cause mortality among prevalent hemodialysis patients. METHODS: The HEMO study was a randomized multicenter study evaluating the effects of high-dose vs. standard-dose and high-flux vs. low-flux hemodialysis on mortality. We measured intact FGF23 levels in stored serum samples at baseline and annually among 919 HEMO participants and identified FGF23 trajectories using group-based modeling. Logistic regression determined predictors of trajectories. Cox regression models evaluated the association between trajectory and all-cause mortality. RESULTS: We identified 5 distinct FGF23 trajectory groups during the initial 24 months: low stable, low increasing, elevated increasing, elevated decreasing, and elevated stable. In multivariable models, diabetes, high dose dialysis, no venous catheter, low serum calcium, phosphorus, and interleukin-6, no vitamin D analog use, and greater residual kidney function were associated with the low stable trajectory group compared to the elevated stable group. High flux dialysis, no venous catheter, and low serum phosphorus and 25-hydroxyvitamin D were associated with the elevated decreasing trajectory group compared to the elevated stable group. After full adjustment, the low stable trajectory group was associated with reduced mortality (hazard ratio [HR] 0.61; 95% CI -0.41-0.91) compared to the elevated stable trajectory group. CONCLUSIONS: We identified 5 distinct FGF23 trajectories over 24 months among HEMO study participants including a decreasing trajectory. The low stable FGF23 trajectory was associated with a reduced HR of all-cause mortality.

Deoxycholic Acid, a Metabolite of Circulating Bile Acids, and Coronary Artery Vascular Calcification in CKD.

BACKGROUND: Vascular calcification is common among patients with chronic kidney disease (CKD), and it is associated with all-cause and cardiovascular disease mortality. Deoxycholic acid, a metabolite of circulating bile acids, is elevated in CKD and induces vascular mineralization and osteogenic differentiation in animal models. STUDY DESIGN: Cohort analysis of clinical trial participants. SETTING & PARTICIPANTS: 112 patients with moderate to severe CKD (estimated glomerular filtration rate, 20-45mL/min/1.73m2) who participated in a randomized controlled study to examine the effects of phosphate binders on vascular calcification. PREDICTOR: Serum deoxycholic acid concentration. OUTCOMES: Baseline coronary artery calcification (CAC) volume score and bone mineral density (BMD) and change in CAC volume score and BMD after 9 months. MEASUREMENTS: Deoxycholic acid was assayed in stored baseline serum samples using liquid chromatography-tandem mass spectrometry, CAC was measured using a GE-Imitron C150 scanner, and BMD was determined using computed tomographic scans of the abdomen with calibrated phantom of known density. RESULTS: Higher serum deoxycholic acid concentrations were significantly correlated with greater baseline CAC volume and lower baseline BMD. After adjusting for demographics, coexisting illness, body mass index, estimated glomerular filtration rate, and concentrations of circulating markers of mineral metabolism, including serum calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23, a serum deoxycholic acid concentration > 58ng/mL (the median) was positively associated with baseline CAC volume (ß=0.71; 95% CI, 0.26-1.16; P=0.003) and negatively associated with baseline BMD (ß = -20.3; 95% CI, -1.5 to -39.1; P=0.04). Serum deoxycholic acid concentration > 58ng/mL was not significantly associated with change in CAC volume score after 9 months (ß=0.06; 95% CI, -0.09 to 0.21; P=0.4). The analysis for the relationship between baseline deoxycholic acid concentrations and change in BMD after 9 months was not statistically significant, but was underpowered. LIMITATIONS: The use of nonfasting serum samples is a limitation because deoxycholic acid concentrations may vary based on time of day and dietary intake. Few trial participants with complete data to evaluate the change in CAC volume score (n=75) and BMD (n=59). No data for changes in deoxycholic acid concentrations over time. CONCLUSIONS: Among patients with moderate to severe CKD, higher serum deoxycholic acid concentrations were independently associated with greater baseline CAC volume score and lower baseline BMD.

Effects of Vitamin D2 Supplementation on Vitamin D3 Metabolism in Health and CKD.

BACKGROUND AND OBJECTIVES: Vitamin D supplements are prescribed to correct low circulating concentrations of 25-hydroxyvitamin D. In CKD, vitamin D metabolism is complicated by decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by CYP27B1 and possibly decreased conversion of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D by CYP24A1. The aim of this study was to determine the effects of vitamin D2 supplementation on vitamin D metabolism in health and CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a treatment-only intervention study of 25 individuals with CKD (eGFR<60 ml/min per 1.73 m2) and 44 individuals without CKD from three academic centers, all with screening 25-hydroxyvitamin D <30 ng/ml. Each participant was prescribed vitamin D2 (ergocalciferol) 50,000 IU orally twice weekly for 5 weeks. We tested whether changes in plasma concentrations of vitamin D metabolites and vitamin D metabolic ratios differed by CKD status. Plasma 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio were calculated as estimates of CYP27B1 and CYP24A1 function, respectively. RESULTS: With treatment, plasma 25-hydroxyvitamin D2 and total 25-hydroxyvitamin D concentrations increased similarly for participants with and without CKD. For participants without CKD, 1,25-dihydroxyvitamin D2 increased (2.8±1.3-32.9±1.4 pg/ml), whereas 1,25-dihydroxyvitamin D3 decreased (45.6±1.9-14.6±1.9 pg/ml), resulting in no significant change in total 1,25-dihydroxyvitamin D; 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio decreased (3.0±0.2-1.7±0.2 pg/ng), and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio increased (115.7±7.8-195.2±7.9 pg/ng). Individuals with CKD had lower baseline levels and smaller changes in magnitude for 1,25-dihydroxyvitamin D2 (2.1±1.6-24.4±1.6 pg/ml; P interaction =0.01), 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio (1.8±0.2-1.1±0.2 pg/ng; P interaction =0.05), and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio (72.0±9.1-110.3±9.3 pg/ng; P interaction <0.001). Fibroblast growth factor-23 and parathyroid hormone were not significantly changed in either group. CONCLUSIONS: Vitamin D2 supplementation decreases conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 and induces vitamin D3 catabolism as evidenced by changes in D3 metabolites and vitamin D metabolic ratios. These effects occur without significant changes in fibroblast growth factor-23 or parathyroid hormone and are blunted in CKD. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_02_CJASNPodcast_17_09.mp3.

Acid Load and Phosphorus Homeostasis in CKD.

BACKGROUND: The kidneys maintain acid-base homeostasis through excretion of acid as either ammonium or as titratable acids that primarily use phosphate as a buffer. In chronic kidney disease (CKD), ammoniagenesis is impaired, promoting metabolic acidosis. Metabolic acidosis stimulates phosphaturic hormones, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) in vitro, possibly to increase urine titratable acid buffers, but this has not been confirmed in humans. We hypothesized that higher acid load and acidosis would associate with altered phosphorus homeostasis, including higher urinary phosphorus excretion and serum PTH and FGF-23. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 980 participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTORS: Net acid excretion as measured in 24-hour urine, potential renal acid load (PRAL) estimated from food frequency questionnaire responses, and serum bicarbonate concentration < 22 mEq/L. OUTCOME & MEASUREMENTS: 24-hour urine phosphorus and calcium excretion and serum phosphorus, FGF-23, and PTH concentrations. RESULTS: Using linear and log-linear regression adjusted for demographics, kidney function, comorbid conditions, body mass index, diuretic use, and 24-hour urine creatinine excretion, we found that 24-hour urine phosphorus excretion was higher at higher net acid excretion, higher PRAL, and lower serum bicarbonate concentration (each P<0.05). Serum phosphorus concentration was also higher with higher net acid excretion and lower serum bicarbonate concentration (each P=0.001). Only higher net acid excretion associated with higher 24-hour urine calcium excretion (P<0.001). Neither net acid excretion nor PRAL was associated with FGF-23 or PTH concentrations. PTH, but not FGF-23, concentration (P=0.2) was 26% (95% CI, 13%-40%) higher in participants with a serum bicarbonate concentration <22 versus ≥22 mEq/L (P<0.001). Primary results were similar if stratified by estimated glomerular filtration rate categories or adjusted for iothalamate glomerular filtration rate (n=359), total energy intake, dietary phosphorus, or urine urea nitrogen excretion, when available. LIMITATIONS: Possible residual confounding by kidney function or nutrition; urine phosphorus excretion was included in calculation of the titratable acid component of net acid excretion. CONCLUSIONS: In CKD, higher acid load and acidosis associate independently with increased circulating phosphorus concentration and augmented phosphaturia, but not consistently with FGF-23 or PTH concentrations. This may be an adaptation that increases titratable acid excretion and thus helps maintain acid-base homeostasis in CKD. Understanding whether administration of base can lower phosphorus concentrations requires testing in interventional trials.

Genetic African Ancestry and Markers of Mineral Metabolism in CKD.

BACKGROUND AND OBJECTIVES: Disorders of mineral metabolism are more common in African Americans with CKD than in European Americans with CKD. Previous studies have focused on the differences in mineral metabolism by self-reported race, making it difficult to delineate the importance of environmental compared with biologic factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional analysis of 3013 participants of the Chronic Renal Insufficiency Cohort study with complete data, we compared markers of mineral metabolism (phosphorus, calcium, alkaline phosphatase, parathyroid hormone, fibroblast growth factor 23, and urine calcium and phosphorus excretion) in European Americans versus African Americans and separately, across quartiles of genetic African ancestry in African Americans (n=1490). RESULTS: Compared with European Americans, African Americans had higher blood concentrations of phosphorus, alkaline phosphatase, fibroblast growth factor 23, and parathyroid hormone, lower 24-hour urinary excretion of calcium and phosphorus, and lower urinary fractional excretion of calcium and phosphorus at baseline (P<0.001 for all). Among African Americans, a higher percentage of African ancestry was associated with lower 24-hour urinary excretion of phosphorus (Ptrend<0.01) in unadjusted analyses. In linear regression models adjusted for socio-demographic characteristics, kidney function, serum phosphorus, and dietary phosphorus intake, higher percentage of African ancestry was significantly associated with lower 24-hour urinary phosphorus excretion (each 10% higher African ancestry was associated with 39.6 mg lower 24-hour urinary phosphorus, P<0.001) and fractional excretion of phosphorus (each 10% higher African ancestry was associated with an absolute 1.1% lower fractional excretion of phosphorus, P=0.01). CONCLUSIONS: A higher percentage of African ancestry was independently associated with lower 24-hour urinary phosphorus excretion and lower fractional excretion of phosphorus among African Americans with CKD. These findings suggest that genetic variability might contribute to racial differences in urinary phosphorus excretion in CKD.

Daily variability in mineral metabolites in CKD and effects of dietary calcium and calcitriol.

BACKGROUND AND OBJECTIVES: Primary prevention of disordered mineral metabolism in CKD necessitates knowledge of its early pathophysiology. This study evaluated daily fluctuations in mineral metabolites in patients with CKD stages 3 and 4 before and after short-term calcitriol treatment and tested the effects of dietary calcium and calcitriol supplementation on these parameters in the dynamic postprandial setting. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twelve CKD patients received calcitriol (0.25 µg daily for 1 week) with hourly assessments of mineral metabolites made throughout the day and in the context of standardized meals before and after treatment. Calcium content (250 versus 500 mg) in the breakfasts constituted the dietary calcium intervention. Twelve healthy volunteers were used as controls. RESULTS: At baseline, compared with controls, fasting CKD subjects had higher parathyroid hormone and fibroblast growth factor 23 levels and greater fractional excretion of phosphate. After breakfast, urinary calcium excretion increased and parathyroid hormone levels dipped transiently in both groups, but they rose soon thereafter, reaching higher peaks in CKD. Calcitriol decreased fasting parathyroid hormone levels, and when combined with dietary calcium load, it normalized the postprandial parathyroid and calcemic responses. Daily variability in mineral metabolites was preserved in CKD before and after calcitriol. Fibroblast growth factor 23 levels increased after calcitriol, although the response was heterogeneous. CONCLUSIONS: Short-term treatment with calcitriol and dietary calcium supplementation normalizes the parathyroid and calcemic postprandial responses in patients with CKD, in whom the diurnal rhythms of mineral metabolites are preserved. Future studies should investigate the variable fibroblast growth factor 23 response to calcitriol in CKD.

Impact of poverty on serum phosphate concentrations in the Third National Health and Nutrition Examination Survey.

OBJECTIVE: Increased serum phosphate is associated with adverse health outcomes. High intake of inexpensive processed and fast foods is common in impoverished communities, and is linked with excessive dietary phosphorus intake and elevated serum phosphate concentrations in chronic kidney disease patients. We examined the impact of socioeconomic status on dietary phosphorus intake and serum phosphate concentrations in the general population. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 14,261 adult participants in the Third National Health and Nutrition Examination Survey. PREDICTORS AND OUTCOMES: Poverty to income ratio (PIR; family income indexed to the federal poverty level) was the primary index of socioeconomic status. Serum phosphate was the primary outcome variable. RESULTS: Although estimated phosphorus intake decreased with decreasing quartiles of PIR (P < .001), serum phosphate was inversely associated with PIR (P = .003). The relationship between lower PIR and higher serum phosphate remained significant after adjustment for demographic, laboratory, and dietary intake characteristics (P = .02). Compared with participants in the highest PIR quartile (income >300% of the federal poverty level), participants in the lowest quartile (income < the federal poverty level) had more than twice the odds of hyperphosphatemia (≥ 4.4 mg/dL) in unadjusted and multivariable-adjusted logistic regression analyses (OR, 2.2; 95% CI, 1.5 to 3.2). CONCLUSIONS: Although lower income was associated with decreased estimated phosphorus intake, increasing poverty was independently linked with increased serum phosphate and higher likelihood of hyperphosphatemia. These findings may indicate that conventional dietary instruments underestimate phosphorus intake, especially among impoverished individuals. Further studies are needed to explore these possibilities.

A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.

The diagnosis of chronic kidney disease (CKD) confers dismal clinical outcomes regardless of whether patients are initiating dialysis and face a median survival of only 2-3 years or they have earlier-stage CKD and face a risk of death that is greater than the risk of progression to dialysis. These poor outcomes are driven by extraordinarily high rates of cardiovascular disease that historically have not responded to risk-factor modification strategies proven to attenuate risk in the general population. Nor have measures aimed at increasing the dose or quality of dialysis made an appreciable dent in mortality. Still worse, interventions that were expected to be beneficial resulted in increased mortality in recent trials. Although this apparent lack of progress in advancing the care of CKD is discouraging, resignation is not an option. On the contrary, with the rising rates of CKD worldwide, there is an urgent need to rigorously test novel therapeutic strategies in randomized trials. The breadth of accumulating evidence linking disordered phosphorus metabolism to adverse outcomes spans in vitro, animal, and human studies, and positions phosphorus management as an attractive target for intervention. Although opinion-based practice guidelines promote phosphorus management strategies that are widely accepted in dialysis patients, there is a clear need to perform randomized controlled trials to prove or disprove the benefits of therapy. Perhaps even more important, the discovery of fibroblast growth factor 23 (FGF23) and its potential as a novel diagnostic to identify disordered phosphorus metabolism at an early, subclinical state has presented the opportunity to develop placebo-controlled randomized trials in pre-dialysis CKD patients with normal serum phosphate levels. This commentary considers the justification and challenges for such trials and presents a 'first-draft' blueprint of distinct trial approaches to initiate a dialog that will ultimately culminate in studies aimed at improving survival across the spectrum of CKD.

Klotho variants and chronic hemodialysis mortality.

Patients with end-stage renal disease (ESRD) suffer exceptionally high mortality rates in their first year of chronic hemodialysis. Both vitamin D and fibroblast growth factor (FGF)-23 levels correlate with survival in these patients. Klotho is a protein in the vitamin D/FGF-23 signaling pathway that has been linked with accelerated aging and early mortality in animal models. We therefore hypothesized that genetic variation in the Klotho gene might be associated with survival in subjects with ESRD. We tested the association between 12 single nucleotide polymorphisms (SNPs) in the Klotho gene and mortality in a cohort of ESRD patients during their first year on hemodialysis (n = 1307 white and Asian). We found a significant association between the CC genotype of one tag SNP, rs577912, and increased risk for 1-yr mortality (RR, 1.76; 95% CI, 1.19-2.59; p = 0.003). This effect was even more marked among patients who were not treated with activated vitamin D supplementation (HR, 2.51; 95% CI, 1.18-5.34; p = 0.005). In lymphoblastoid cell lines derived from HapMap subjects, the CC genotype was associated with a 16-21% lower Klotho expression compared with the AA/AC genotype. Our data suggest that a specific Klotho variant (rs577912) is linked to survival in ESRD patients initiating chronic hemodialysis and that therapy with activated vitamin D may modify this risk.

Phosphorus binders and survival on hemodialysis.

Although hyperphosphatemia is a risk factor for mortality, there are limited data on whether therapy with phosphorus binders affects survival. We analyzed a prospective cohort study of 10,044 incident hemodialysis patients using Cox proportional hazards analyses to compare 1-yr all-cause mortality among patients who were or were not treated with phosphorus binders. We performed intention-to-treat analyses to compare patients who began treatment with phosphorus binders during the first 90 d after initiating hemodialysis (n = 3555) with those who remained untreated during that period (n = 5055). We also performed as-treated analyses that modeled phosphorus binder treatment as a time-dependent exposure. We compared survival in a subcohort of treated (n = 3186) and untreated (n = 3186) patients matched by their baseline serum phosphate levels and propensity score of receiving phosphorus binders during the first 90 d. One-year mortality was 191 deaths/1000 patient-years at risk. Treatment with phosphorus binders was independently associated with decreased mortality compared with no treatment in the intention-to-treat, as-treated, and matched analyses. The results were independent of baseline and follow-up serum phosphate levels and persisted in analyses that excluded deaths during the first 90 d of hemodialysis. In summary, treatment with phosphorus binders is independently associated with improved survival among incident hemodialysis patients. Although confirmatory studies are needed in the dialysis setting, future placebo-controlled, randomized trials of phosphorus binders might focus on predialysis patients with chronic kidney disease and normal serum phosphate levels.

Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD.

Normophosphatemia and normocalcemia are maintained in chronic kidney disease (CKD) by increased levels of fibroblast growth factor-23 (FGF-23) and parathyroid hormone (PTH), but the stimuli for secretion of these hormones in early CKD are incompletely understood. Most human physiologic studies have focused on random or fasting measurements of phosphorus, calcium, FGF-23, and PTH, but in this study, the hypothesis was that measurements in the postprandial state may reveal intermittent stimuli that lead to increased FGF-23 and PTH levels. The 4-h postprandial response in 13 patients with CKD and fasting normophosphatemia and normocalcemia (mean GFR 41 +/- 8 ml/min per m(2)) was compared with 21 healthy volunteers. Compared with healthy subjects, fasting patients with CKD had significantly higher levels of FGF-23 and fractional excretion of phosphorus; lower fractional excretion of calcium; and no difference in serum calcium, phosphorus, and PTH levels. After standardized meals, urinary phosphorus excretion in both groups increased despite unchanged serum phosphorus and FGF-23 levels. Postprandial urinary calcium excretion also increased in both groups, and this was accompanied by significantly reduced serum calcium and increased PTH levels in patients with CKD only; therefore, FGF-23 does not seem to be an acute postprandial regulator of phosphaturia in CKD or in health, but inappropriate postprandial calciuria with episodic, relative hypocalcemia may represent a previously unreported mechanism of secondary hyperparathyroidism in CKD.